Tourette Syndrome (TS) and its associated conditions (tics, OCD, ADHD) constitute a substantial societal burden, as TS alone is estimated to affect nearly 1% of the population. A critical barrier to progress in understanding the mechanisms for these disorders is the lack of animal models with etiological relevance to the human condition. We propose to take advantage of the recent discovery of a genetic etiology for TS involving a nonsense mutation within the histidine decarboxylase gene to overcome this barrier. In this proposal we will create, validate and behaviorally characterize a novel mouse model for TS. To most faithfully replicate the protein-based pathobiology as it occurs in humans, we will create humanized mouse models that express the human protein in place of the endogenous mouse protein. Moreover, because such a model will express the human TS mutant protein, once validated, this mouse model will be uniquely suited for screening novel therapeutics in a way that is not afforded by conventional mouse knockin approaches. PUBLIC HEALTH RELEVANCE: The lack of animal models for Tourette Syndrome and its associated conditions of tics, obsessive compulsive disorder, and attention-deficit hyperactivity disorder present a substantial barrier to progress in identifying the underlying mechanisms for these conditions as well as for preclinical testing of candidate therapies. This proposal aims to develop a mouse model for Tourette Syndrome based on a human genetic etiology involving a nonsense mutation within the histidine decarboxylase gene. This mouse model will provide a previously unavailable reagent with human etiological relevance. To most faithfully replicate the human pathogenesis, the modified gene will be altered to encode the human protein, making this mouse model also uniquely suited for drug development and screening programs that target the human HDC protein.